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Antiphospholipid Syndrome

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Antiphospholipid antibody Syndrome:
Introduction
Diagnosis
Treatment

ANTIPHOSPHOLIPID ANTIBODIES (APLA)

APLA are antibodies directed against certain phospholipids. They are found in variety of clinical senerios. APLA are associated with a syndrome that includes a hypercoagulable state, thrombocytopenia, fetal loss, strokes, dementia, optic changes, Addison's disease, & certain skin rashes.

HISTORY
First described by Conley in the 1950's when some patients with lupus were noted to have prolonged APTT. Later, an association with false positive VDRLs was also noted. Despite the elevation of the aPTT it was observed that patients did not develop hemorrhagic complications unless they also had hypoprothrombinemia or thrombocytopenia.
Bowie first described the association of APLA & thrombosis in 1964. Feinstein & Rapaport in an 1972 review called it the "lupus anticoagulant".
Harris, recognizing that cardiolipin is a major component of the VDRL test, developed the anticardiolipin (ACLA) antibody test.
It also became well recognized that patients without SLE could also develop symptomatic disease from APLA.

No one really knows what the underlying pathogenic mechanism is that leads to the clinical syndrome.
 
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Epidemiology:

30-50% of patients with SLE will develop APLA.
APLA can also be found in patients with other autoimmune diseases.
Patients without lupus or other autoimmune disease can have symptomatic APLA ("Primary APLA syndrome").
Children can develop transient APLA after viral infections. These often come to clinical attention during pre-operative evaluation for tonsillectomy.
Near 30% of patients with HIV infection will develop APLA.
However, the infection associated APLA are not associated with thrombosis.

In screening studies of blood donors, up to 8% of normal people will have APLA. However the APLA in these people are usually low titer and most often occur in young women.
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Medications may also induce APLA:

Chlorpromazine
procainamide,
dilantin
quinidine.
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TESTS FOR ANTIPHOSPHOLIPID ANTIBODIES (APLA)

There are two main groups of tests for APLA's: testing for presence of antibodies to cardiolipin and the coagulation based tests for APLA.

Coagulation Based Tests: As you recall, APLA react with phospholipid. Phospholipids are used in coagulation tests to provide a surface for the coagulation reaction to occur. The basis for all these tests is that if there are antibodies binding to the phospholipid, it will interfere with the coagulation reaction and prolong the clotting time. Once an elevated aPTT is found one must verify it is due to an inhibitor by demonstrating it does not correct with a 50:50 mix. This is done by making a mixture of the patient's and normal pool plasma and performing a aPTT on it. Then the mixture is incubated for 30, 60 and 120 minutes and aPTT's are performed at various times. Each of the three major diagnostic considerations will perform differently on the 50:50 mix:

1. Factor Deficiency. aPTT will correct to normal at time 0 and stay in the normal range on each of the time points.

2. APLA. Does not correct to normal (may partially correct) at time 0 or any time point. May actually prolong further. (Lupus cofactor effect).

3. Factor Inhibitors. Corrects to normal at time 0 but then prolongs at next time points.
 
 
TIME (SECONDS) 0 30 60 120
NORMAL POOL 30 32 33 34
PATIENT'S 50 52 55 53
50:50-DEF(1) 30 32 33 34
50:50-APLA(2) 40 38 42 39
50:50-INHIB(3) 30 34 40 55 

After one demonstrates the prolongation of the clotting time and establishes this is do to an inhibitor, then one needs to show its dependance on phospholipids. To do this one adds phospholipid derived from platelets or "hexagonal phase" phospholipids (named for the shape they assume in suspension). APLA bind avidly to both platelet and hexagonal phase" phospholipids. Thus addition of these lipids will correct the prolonged coagulation tests. Factor inhibitors will not correct with platelet phospholipids. To summarize, one screens for APLA with coagulation based tests to see if any test is prolonged. If one test is prolonged, then one uses a 50:50 mix to prove it an inhibitor. Then one uses platelet or hexagonal phospholipids to correct the abnormal clotting time.

aPTT. Only sensitive to 30% of APLA. One can increase sensitivity by using different reagents. Many patients with APLA will have normal aPTT and therefor one cannot exclude APLA by just doing a aPTT.

Dilute Russell Viper Venom Time (dRVVT). This test is very sensitive to any interference with phospholipid because it utilizes very little added phospholipid. It is performed by initiating the coagulation cascade with Russell Viper venom.

Kaolin clotting time. This test uses no added phospholipid and is the most sensitive test to APLA but is very technique demanding.

Platelet Neutralization Test. This test takes a reaction that is prolonged by plasma which does not correct with a 50:50 mix and adds extracts of platelet. If it corrects to normal this is very specific for APLA.

Hexagonal Phase Phospholipid. Same principles as the platelet neutralization test but used hexagonal phase phospholipids. Currently OHSU uses a testing system that corrects for anticoagulation and other factor deficiencies. Thus this is the only valid test for lupus inhibitors when patients are on anticoagulants.
 

Anticardiolipin Antibodies: This is an ELISA test for antibodies to cardiolipin. Therefore, unlike the coagulation based tests, it can be performed on plasma which has been anticoagulated. Tests results at OHSU is reported in standard deviation with >3SD abnormal. Tests are also reported as specific isotype (IgG, IgA, IgM). It is still debatable if specific isotypes are associated with different patterns of disease. The antibodies that react with cardiolipin are different ones then those which cause the lupus inhibitor effect. Only 60% of patients with APLA will have both ACLA and lupus inhibitors. Consequently one needs to assay for both in assessing patients for APLA. Recently is has been discovered that the ACLA actually react with a complex of a cardiolipin and protein known as beta-2-glycoprotein. ACLA tests utilizing this complex are being tested to see if they provide more clinical information then the routine APLA.
 

Approach to the patients suspected of having APLA. Unfortunately there is no one test that can screen a patient for APLA. One must do the whole panel on patients suspected with APLA. A good screen is to perform the hexagonal phospholipid assay and ACLA assay. If these are negative and one is very suspicious then one order further tests. These would include 1) Anticardiolipin antibodies, 2) Kaolin clotting time 3) dRVVT 4)"Lupus Inhibitor Screen" (different aPTT reagents). At OHSU the dRVVT is done along with the "Lupus Inhibitor Screen". One caveat in testing is that levels of APLA may fall during thrombotic events.
 

SEMANTICS

Semantically patients with APLA and one "major clinical criteria" are said to have "APLA syndrome". The major clinical criteria include venous or arterial thrombosis (including neurological disease), thrombocytopenia, or frequent miscarriages. Primary APLA syndrome is APLA syndrome occurring outside the setting of lupus. In distinction to SLE-APLA patients, primary APLA patients are more often male and will have low titer ANA's but no other criteria for SLE. Also "lupus anticoagulant" and "lupus inhibitor" tend to be used interchangeable for APLA which prolong the aPTT.
 

APLA: CLINICAL ASSOCIATIONS

APLA are associated with a variety of disease states. The best described are venous thrombosis, arterial thrombosis, neurological disease, frequent miscarriages and thrombocytopenia
 

Venous Thrombosis. Venous thrombosis was the first described manifestation of APLA and still one of the most clinically predominant. Overall, retrospective studies show that 31% of patient with APLA have venous thrombosis. Patients with lupus and SLE have a thrombosis rate of 42% while those with infections and drug-induced APLA the rate is less then five percent. Patients with APLA are over represented in young patients with deep vein thrombosis. Prospective studies have demonstrated a relative risk for venous thrombosis of 5.3 for patients with IgG ACLA. Patients with APLA venous thrombosis can be difficult to treat. Many patients (?1/3-1/2) are resistant to low intensity warfarin (INR 2.0-3.0) and need to be treated with high intensity warfarin therapy (INR= 2.5-3.5) or chronic subcutaneous heparin. These patients have high rates of recurrent thrombosis if anticoagulation is stopped with recurrence rates of 20-50%/year of repeat thromboses have been reported if therapy is stopped. Rarely patients may be refractory to warfarin and will need to be on long-term heparin therapy.
 

Arterial Disease. APLA are increased in young patients with myocardial infarctions and strokes. They are also found in higher proportion in patients with peripheral vascular disease and may predict graft failure. Prospective studies have demonstrated that patients have APLA have higher rates of saphenous by-pass vein occlusion and re-occlusion of PTCA. One confounding factor is that anticardiolipin antibodies will cross-react with oxidized-LDL. Since raised levels of ox-LDL are found in patients with atherosclerosis the anticardiolipin antibodies sometimes found in these patients may be an epiphenomenon of their atherosclerosis.
 

Neurological Disease. A variety of neurological disorders have been associated with APLA. The underlying cause of these symptoms appear to be thrombosis. Some patients have large vessel disease while many patient have small vessel involvement. Patients with APLA often will have multiple MRI abnormalities consistent with small white matter infarcts. The neurological diseases include:

Strokes. APLA is found 10-46% of young patients with strokes and in 10% of stroke patients overall. Stroke patients with APLA tend to be younger (42 years vs 62 years). These patient also have a recurrence rate of 6-30%/year and a mortality rate of 10%/year. Certain groups of patients appear to be at even higher recurrence rates. These would include SLE patients with APLA and patients with Sneddon's syndrome (described below).

Early-Onset Dementia. This is becoming a more recognized and feared feature of APLA. Thirty-five patients with APLA and dementia are followed at OHSU and dozens are reported in the literature. The dementia is multi-infarct in nature and occurs often without a history of major stroke episodes. APLA-related dementia on the average occurs a decade earlier (52 years) than non-APLA dementia. Sneddon's syndrome is a combination of livedo reticularis and cerebral ischemic events. It is a form of APLA that often results in major morbidity and mortality. The skin involvement in Sneddon's may be severe enough to result in ulceration. Patients with Sneddon's syndrome seem also to have a higher incidence of thrombocytopenia.

Ocular Events. Amaurosis fugax, retinal artery and vein thrombosis have been reported in multiple case reports to be a part of the APLA syndrome.

Other. APLA are found in as many as 50% of patients who get migraines. As will be discussed below, patients may have encephalopathy as part of severe APLA.
 

Fetal Loss. Fetal loss is seen in 38% of SLE patients with APLA. The incidence of fetal loss in non-SLE APLA is controversial. When women who have recurrent fetal loss (>3) are screened the incidence of APLA is 30%. The pathophysiology is thought to be due to micro-thrombosis in the placenta.
 

Thrombocytopenia. Certain APLA will react with activated platelets leading to thrombocytopenia. Since it is only activated platelets that expose the proper epitopes, often it is the patients with the thrombotic manifestations of APLA who will also get the thrombocytopenia. The treatment of these patients is clinically challenging since the thrombocytopenia often occurs in patients who are anticoagulated for thrombosis. Danazol appears to be uniquely effective for these patients.
 

Hypoprothrombinemia Patients with APLA (almost always ones with lupus inhibitors) may have an elevated prothrombin time (PT) for 2 reasons. One is that the APLA are present in such high titer that will also interfere with the PT test. The other is that 10% of patients with lupus inhibitors will develop non-neutralizing antibodies to prothrombin. This leads to increased clearance of prothrombin from the plasma and hypoprothrombinemia. Since patients with hypoprothrombinemia can present with hemorrhagic complications, it is important to check for this when one is faced with an APLA patient with an elevated PT. This can be done by doing a 50:50 mix on the PT and measuring the plasma level of prothrombin. Plasma infusions and steroids are effective in raising the prothrombin levels in patients with prothrombin antibodies.
 

Other Associated Diseases. Patients with APLA may have an assortment of skin findings included livedo, Raynaud's phenomena, ulcers, and superficial thrombophlebitis. Up to 26% of patients with SLE and APLA have cardiac valve vegetations and mitral regurgitation. Rarely patient have had valve destruction so extensive as to have required valve replacement. Myocardial dysfunction is seen in 5% of SLE-APLA patients. Primary pulmonary hypertension has been associated with APLA. Ten percent of patients with chronic thromboembolic pulmonary hypertension have APLA. Adrenal insufficiency from microvascular thrombosis has been seen also in APLA patients.
 

CATASTROPHIC APLA

Rarely patients with APLA can present with fulminate multiorgan system failure. This is cause by widespread microthrombi in multiple vascular fields. These patient will present with renal failure, encephalopathy, ARDS (often with pulmonary hemorrhage), cardiac failure, dramatic livido reticularis, and thrombocytopenia. Many of these patients have pre-existing autoimmune disorders. It appears that the best therapy for these patients is aggressive immunosuppression with plasmapheresis then (perhaps) IV cyclophosphamide monthly. Early recognition of this syndrome can lead to quick therapy and resolution of the multiorgan system failure.
 
 

THERAPY

Although there are no prospective trials of therapy in APLA, one can draw several lessons from what has been found in retrospective studies. Despite APLA being seemingly an autoimmune disease, immunosuppression does not prevent recurrent thrombosis, fetal loss, or neurological syndromes and should not play a role in the therapy of thrombotic APLA. The only exception to this is may be "catastrophic APLA" where plasmapheresis may play a crucial role. Low intensity anticoagulation with warfarin appears to be effective in most patients with APLA except patients with venous thrombosis. As mentioned above, many of the patients will fail low intensity warfarin and need more aggressive anticoagulation. Despite initial enthusiasm for aspirin and prednisone for prevention of miscarriages in pregnant women with APLA, it now appears that heparin anticoagulation is more effective.
 

Arterial Thrombosis: Warfarin to an INR of 2.0 - 3.0

Venous Thrombosis: Warfarin to an INR of 3.0 - 3.5. Patients who "break through" warfarin should receive heparin.

Pregnancy and APLA: Most controversial. One approach is based on previous history. If their is a history of thrombosis one should use LMW heparin in therapeutic doses throughout the pregnancy. For frequent miscarriage some advocate either prophylactic heparin with one aspirin a day or therapeutic heparin alone.
 

Difficulties in monitoring anticoagulation

Since APLA react with phospholipid both the aPTT and the protime can be affected. If one uses standard heparin to anticoagulate patients with APLA one needs to monitor with heparin levels (0.35 - 0.70 anti-Xa units 6 hours after the shot). The predictable dosing and anticoagulant effect is one advantage of using LMW heparin acutely for thrombosis in APLA patients. One should measure LMW heparin levels in patients with APLA for long term therapy (0.7 - 1.0 anti-Xa units) or those patients with renal failure.

Often patients with APLA will have minor elevations of their protime. Those few patients with elevated protimes due to the inhibitor can be very difficult to manage with warfarin. One option is to perform prothrombin and proconvertin times ("P&P") to follow anticoagulation. The P&P is less dependent on phospholipids and one can monitor therapy. The other option is to use long-term heparin.
 

One difficult issue it what to do with the patient with APLA but no thrombotic manifestations. Although some of these patients are at risk, especially those with SLE, many will never develop thrombosis. The current recommendation would be to do very careful search for thrombosis. This would include a brain MRI in patients with SLE and in patients with any neurological symptom. If this work-up is negative then the patient is followed very closely.
 

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TREATMENT

Treatment of patients with hypercoagulability associated with antiphospholipid syndrome requires special considerations. The presence of laboratory abnormalities indicative of the syndrome in the absence of clinical evidence of disease does not mandate treatment. When anticoagulation is needed, warfarin is used.[63] In high-risk situations such as postoperative states, heparin compounds can be used before warfarin. The addition of steroids or immunosuppressive agents is of unproven benefit in the antiphospholipid syndrome. Nonetheless, sometimes it is used, especially if clinical and laboratory parameters are available to judge effectiveness. During pregnancy in a patient with antiphospholipid syndrome, subcutaneous heparin, LMWH, steroids, or aspirin can be tried. If fetal loss occurs despite these efforts, then the use of intravenous gammaglobulin for future pregnancies may be necessary. Of course, warfarin is contraindicated in pregnancy.

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